This proposal details a 5-year training program and is designed to prepare the principal investigator for a career in academic medicine. The principal investigator has fulfilled clinical requirements for internal medicine at the Johns Hopkins Hospital and cardiology fellowship at Brigham and Women's Hospital. The program encourages the acquisition of sound principles and expertise for studying the transcriptional co-activator, PPAR gamma co-activator 1 alpha (PGC1-alpha), as it pertains to metabolism. Bruce M. Spiegelman, Ph.D. is a pioneer in the field of energy metabolism and will mentor the principal investigator by providing career and scientific guidance. The research endeavors to elucidate the role of the PGC1-alpha holo-complex in diabetes and energy metabolism. Prior genetic studies in the laboratory identified several transcription factors regulated by PGC1- alpha and highlighted the pivotal role of PGC1-alpha in energy homeostasis. The proteome is the final determinant of cellular phenotype, and we hypothesize that characterization of the PGC1-alpha holo-complex will identify novel factors that regulate diabetes and energy metabolism. Specific aims of the project are: 1) Establish a versatile technique to isolate PGC1-alpha holo-complexes. 2) Elucidate the proteins comprising the PGC1-alpha holo-complex from normal and diabetic tissues. 3) Characterize the molecular and biological significance of the PGC1-alpha complex. This study constitutes the first functional and proteomic analysis of the PGC1-alpha holo-complex, and may define new regulatory roles for PGC1-alpha in diabetes. The department of Cancer Biology at the Dana-Farber Cancer Institute provides a stimulating and scientifically sound base from which the principal investigator can build a career in academic medicine. Ultimately, the environment and the program will foster the development of the principal investigator into an independent physician-scientist.